1. Field of the Invention
The present invention relates to systems and methods for treating a condition associated with a mucosal surface, such as the vaginal part of the cervix. In particular, the systems and methods may involve an immune response modifier (IRM) compound chosen from imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof. In one optional embodiment, the invention provides systems and methods which are particularly advantageous for topical application to the cervix for treatment of cervical conditions such as cervical dysplasias including dysplasia associated with human papillomavirus (HPV).
The present invention is also directed to medicament delivery arrangements and methods of use. Some aspects of the invention are directed to the delivery of a pharmacological agent to a selected location with minimal delivery to regions surrounding the selected location. In some optional embodiments the invention is particularly advantageous for topical delivery of a pharmacological agent to the uterine cervix.
2. Background of the Invention
Many imidazoquinoline amine, imidazopyridine amine, 6,7-fused cycloalkylimidazopyridine amine, 1,2-bridged imidazoquinoline amine, thiazolo- and oxazolo-quinolinamines and pyridinamines, imidazonaphthyridine and tetrahydroimidazonaphthyridine amine compounds have demonstrated potent immunostimulating, antiviral and antitumor (including anticancer) activity, and have also been shown to be useful as vaccine adjuvants to enhance the protective immune system response to vaccines. These compounds are hereinafter sometimes collectively referred to as the xe2x80x9cIRMxe2x80x9d (immune response modifier) compounds of the invention. An IRM compound may be selected from the group comprising imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines 1,2-bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof. Methods for preparing such IRMs and pharmaceutical compositions containing them are disclosed in, for example, U.S. Pat. Nos. 4,689,338; 5,389,640; 5,268,376; 4,929,624; 5,266,575; 5,352,784; 5,494,916; 5,482,936; 5,346,905; 5,395,937; 5,238,944; 5,525,612; 5,175,296; 5,693,811; 5,741,908; 5,939,090; 6,110,929; 4,988,815; 5,376,076; and PCT Publications WO 99/29693; WO 00/76505; WO 00/76518; and WO 00/76519. The entire disclosure of each of these patents and patent applications is incorporated herein by reference.
The immunostimulating, antiviral and antitumor activities of these compounds have been discussed in detail, and certain specific diseases have been identified as being susceptible to treatment therewith, including basal cell carcinoma, eczema, essential thrombocythaemia, hepatitis B, multiple sclerosis, neoplastic diseases, psoriasis, rheumatoid arthritis, type I herpes simplex, type II herpes simplex, and warts. One of these IRM compounds, known as imiquimod, has been commercialized in a topical formulation, Aldara(trademark), for the treatment of anogenital warts associated with human papillomavirus.
The mechanism for the antiviral and antitumor activity of these IRM compounds is thought to be due in substantial part to enhancement of the immune response due to induction of various important cytokines (e.g., interferons, interleukins, tumor necrosis factor, etc.). Such compounds have been shown to stimulate a rapid release of certain monocyte/macrophage-derived cytokines and are also capable of stimulating B cells to secrete antibodies which play an important role in these IRM compounds"" antiviral and antitumor activities. One of the predominant immunostimulating responses to these compounds is the induction of interferon (IFN)-xcex1 production, which is believed to be very important in the acute antiviral and antitumor activities seen. Moreover, up regulation of cytokines such as, for example, tumor necrosis factor (TNF), IL-1 and IL-6 also have potentially beneficial activities and are believed to contribute to the antiviral and antitumor properties of these compounds.
Although some of the beneficial effects of IRMs are known, the ability to provide therapeutic benefit via topical application of an IRM for treatment of a particular condition at a particular location may be hindered due to tissue irritation, formulation wash away, poor permeation or undesired systemic delivery of the topically applied compound. Accordingly, there is a need for new methods, formulations, and systems to provide the greatest therapeutic benefit from this class of compounds.
Topical administration of a pharmacological agent to a tissue surface can provide localized therapeutic benefit without concomitant systemic effects. However, topical application is often difficult or impossible due to the anatomical location of the tissue. In some cases, application of the agent to a general anatomical region that includes or surrounds the target tissue may be an alternative to direct topical application. But, if the agent has irritating properties, this alternative disadvantageously carries with it the possibility of irritating tissues surrounding the target tissue. In addition, even if the agent is non-irritating, regional application typically requires use of a greater volume or concentration of the agent to achieve a therapeutic result equivalent to that achieved by direct application to the target tissue.
The uterine cervix is one example of a target tissue to which it is difficult to apply a topical agent. Relative to a standing position, the cervix is typically located at the uppermost portion of the vaginal cavity. However, while the cervix is located at the uppermost portion of the vaginal cavity, age, the stage of the estrous cycle, pregnancy, and other factors cause variability of the location of the cervix between different women and in the same woman at different stages of life.
Certain cervical conditions can be advantageously treated by topical administration of a pharmacological agent. Cervical dysplasia is an example of a pathological condition that can be effectively treated by direct delivery of medication to the surface of the cervix where the abnormal cells are typically found. Unfortunately, most currently available applicators for vaginal drug delivery are inadequate for applying a medication to the surface of the cervix. And, since cervical dysplasia can lead to cervical cancer, an applicator that is less than optimal is not an acceptable option.
Most presently available vaginal applicators are for application to the vaginal cavity generally and not for direct application to the cervix. In general, the length and configuration of the applicators are insufficient to ensure delivery of an agent to the uppermost portion of the vaginal cavity. Delivery to the middle or lower portion of the vagina does not ensure that an agent will reach the cervical tissue in the upper portion of the vagina. In addition, with the exception of certain body orientations, gravity tends to drain agents away from the cervix. Normal discharge and flow of fluids, both menstrual and non-menstrual, also drain away from the cervix. Thus, any applicator that is not capable of repeatedly delivering an appropriate amount of agent to the uppermost end of the vaginal cavity risks less than optimal treatment.
Overcoming the inaccuracy of present vaginal applicators, when used for cervical delivery of an agent, by delivering an excess volume or concentration of the medication may be unacceptable due to the risk of undesired effects to surrounding tissues. However, delivery of reduced volumes or concentrations to avoid irritation to surrounding tissue risks the serious consequences of ineffective treatment.
Accordingly, there is continuing need for improved delivery systems and methods for topical application of a pharmacological agent.
One aspect of the invention includes a system for treating a condition associated with a mucosal surface. The system comprises an immune response modifier (IRM) compound chosen from imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof. The system also comprises an applicator device for applying the IRM compound to the mucosal surface.
Another aspect of the invention includes a system comprising an immune response modifier (IRM) compound chosen from imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof. The system also includes an applicator device for applying to the mucosal surface the IRM compound.
For example, the IRM compound may be 1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine, or 4-amino-xcex1,xcex1-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol or 2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine.
The system may be used for treating a condition associated with the mucosal surface on a cervix, optionally, the vaginal part of the cervix. Exemplary conditions associated with the mucosal surface include cervical dysphasia and cervical intraepithelial neoplasia.
In an exemplary embodiment, the applicator device may comprise a hollow tube and a piston slidably received within the tube.
Yet another aspect of the invention includes a method for treating a condition associated with a mucosal surface. The method comprises providing an immune response modifier (IRM) chosen from imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinolines amines, 1,2-bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof. The method also includes providing an applicator device for applying to the mucosal surface the IRM compound. In addition, the method further includes applying the IRM compound to the mucosal surface with an applicator device.
The method may involve inserting the applicator device into the vagina, positioning a distal end of the applicator device adjacent to the vaginal part of the cervix, and applying the IRM compound to the vaginal part of the cervix.
At least some of the embodiments disclosed herein provide medicament application systems and methods suitable for topical administration of an agent to a target tissue. The systems and methods could be advantageous for intravaginal delivery of a pharmacological formulation. For example, some embodiments provide effective topical application of a pharmacological agent to the cervix for treatment or prevention of conditions including, for example, cervical dysplasia.
Additional aspects will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. It will be appreciated that at several locations throughout the specification, guidance is provided through lists of examples. In each instance, the recited list serves only as a representative group; it is not meant that the list is exclusive.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.